Molecular genetic analysis of normosmic hypogonadotropic hypogonadism in a turkish population: Identification and detailed functional characterization of a novel mutation in the gonadotropin-releasing hormone receptor gene

A. Kemal Topaloglu*, Zhi Liang Lu, I. Sadaf Farooqi, Neslihan O. Mungan, Bilgin Yuksel, Stephen O'Rahilly, Robert P. Millar

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)


Background/Aims: Currently known mutations account for less than 15% of cases with normosmic hypogonadotropic hypogonadism (nIHH). The objective of the study was to identify novel hereditary associations in the pathogenesis of nIHH. Methods: We investigated 26 Turkish patients with nIHH (21 males and 5 females) from 22 families. The coding regions of the GnRH receptor, GnRH1, GPR54, and KISS1 genes were directly sequenced. Results: In two sisters, a novel homozygous missense mutation, R139C, located in the conserved DRS motif at the junction of the third transmembrane and the second intracellular loop of the GnRH receptor was identified. The R139C mutation almost completely abolished plasma membrane expression while having little effect on GnRH-binding affinity. The mutant receptor expression was rescued by a membrane-permeant, non-peptide GnRH receptor antagonist IN3. Conclusions: Consistent with the previous studies we were able to find mutations in only 7.6% of a well-defined group of patients with nIHH, which further suggests that yet unidentified genetic associations to explain nIHH exist.

Original languageEnglish
Pages (from-to)301-308
Number of pages8
Issue number5
Publication statusPublished - Mar 2007
Externally publishedYes


  • Gonadotropin-releasing hormone receptor gene
  • Hypogonadism, normosmic hypogonadotropic
  • Mutation

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